Herpes simplex research includes all medical research that attempts to prevent, treat, or cure herpes, as well as fundamental research about the nature of herpes. Examples of particular herpes research include drug development, vaccines and genome editing. HSV-1 and HSV-2 are commonly thought of as oral and genital herpes respectively, but other members in the herpes family include chickenpox (varicella/zoster), cytomegalovirus, and Epstein-Barr virus. There are many more virus members that infect animals other than humans, some of which cause disease in companion animals (e.g., cats, dogs, horses) or have economic impacts in the agriculture industry (e.g., pigs, cows, sheep, chicken, oysters).
Vaccine research Various vaccine candidates have been developed, the first ones in the 1920s, but none has been successful to date.
Both herpes simplex virus types (HSV-1 and HSV-2) share a high rate of sequence homology, so the development of a prophylactic-therapeutic vaccine that proves effective against one type of the virus would likely aid in the development of the other. , several vaccine candidates are in different stages of clinical trials.
An ideal herpes vaccine should induce immune responses adequate to prevent infection. Short of this ideal, a candidate vaccine might be considered successful if it (a) mitigates primary clinical episodes, (b) prevents colonization of the ganglia, (c) helps reduce the frequency or severity of recurrences, and (d) reduces viral shedding in actively infected or asymptomatic individuals. The fact that a live-attenuated vaccine induced better protection from HSV infection and symptoms is not new, because live-attenuated vaccines account for most of the successful vaccines in use today. However, governmental and corporate bodies seem to support the more recent and safer but possibly less effective approaches such as glycoprotein- and DNA-based vaccines.
Vaccine design Vaccine-elicited protection against HSV is challenging to achieve due to the ability of herpesviruses to evade many aspects of the mammalian immune response. As a general principle, the effectiveness of a HSV vaccine design is often inversely proportional to its safety. Subunit vaccines, which consist of individual or small groups of viral antigens, remove all risk of complications resulting from the production of vaccine-associated infectious viral particles but are limited in the degree and scope of immunity that can be produced in vaccinated individuals. Inactivated vaccines, which consist of intact viral particles, dramatically increase the repertoire of viral antigens that engender the immune response but like subunit vaccines are generally constrained to producing humoral immunity. Like inactivated vaccines, replication-defective vaccines expose the immune system to a diverse swath of HSV antigens but can produce both cellular and humoral immunity because they retain the ability to enter cells by HSV-induced membrane fusion. However, replication-defective HSV vaccines are challenging to produce at scale and offer limited immunization due to the lack of vaccine amplification. Live-attenuated vaccines are highly efficacious, potentially eliciting both cell-mediated and humoral immunity against structural and non-structural viral proteins, but their ability to replicate can result in vaccine-related illness particularly in immunocompromised individuals. Whereas subunit vaccines have proven effective against some viruses, immunity produced by subunit HSV vaccines have failed to protect humans from acquiring genital herpes in several clinical trials. In contrast, the success of the live-attenuated chickenpox vaccine demonstrates that an appropriately live-attenuated α-herpesvirus may be used to safely control human disease. The challenge of achieving vaccines that are both safe and effective has led to two opposing approaches in HSV vaccine development: increasing the efficacy of subunit vaccines (primarily by improving adjuvant formulations), and increasing the safety of live-attenuated vaccines (including the development of "non-invasive" vaccines).
Vaccine candidates
The chart below is an attempt to list all known proposed HSV and varicella zoster vaccines and their characteristics. Please update with any missing information on vaccines only. Vaccine Company & Lead Researcher Vaccine Type Trial Status and Results BNT163 / HSV-2 mRNA Trivalent Vaccine BioNTech in collaboration with Perelman School of Medicine at the University of Pennsylvania Kevin P. Egan, Harvey Friedman, Sita Awasthi Prophylactic HSV-2 mRNA lipid nanoparticle-encapsulated trivalent vaccine (containing gC2, gD2, gE2) In pre-clinical studies the mRNA vaccine prevented death and genital disease in 54/54 (100%) mice infected with HSV-1 and 20/20 (100%) with HSV-2, and prevented infection of the dorsal root ganglia in 29/30 (97%) mice infected with HSV-1 and 10/10 (100%) with HSV-2
First Phase I trial results have shown that BNT163 is well-tolerated with an acceptable safety profile and it induces binding antibody and neutralizing titers to HSV-2 antigens. VC2 Louisiana State University, Rational Vaccines licensed VC2 in 2021 Gus Kousoulas Live-attenuated HSV vaccine with small deletions in UL20 and UL53 R2 Thyreos Inc Gregory Smith, Gary Pickard, Ekaterina Heldwein Prophylactic live-attenuated HSV vaccine mutated in R2 coding region of UL37 HSV-2 ΔgD-2 Albert Einstein College of Medicine / X-Vax Technology William Jacobs Jr & Betsy Harold Prophylactic live-attenuated HSV-2 vaccine with US6 (gD) deleted A direct comparison from 2025 of three herpes simplex virus-2 vaccine candidates showed a robust prophylactic efficiency of HSV-2 ΔgD-2 when the vaccine was given subcutaneously in the neck or intramuscularly in the thigh. Out of 10 mice, all survived an HSV-2 intravaginal infection, only one individual showed moderate disease. HSV-2 gD27 Kening Wang Live-attenuated HSV-2 vaccine with three amino acid mutations in gD A direct comparison from 2025 of three herpes simplex virus-2 vaccine candidates showed a robust prophylactic efficiency of HSV-2 gD27 when the vaccine was given intrarectally or intravaginally. Out of 10 mice, all survived an HSV-2 intravaginal infection and had little or no disease. HSV-2 ICP0‾ HSV-2 0ΔNLS / Theravax / RVx-201 Rational Vaccines William Halford Therapeutic live-attenuated HSV-2 vaccine Rational Vaccines was sued by some study participants. In February 2026 Rational Vaccines has started to gather volunteer information regarding the planned RVx201 vaccine Phase I trial in the UK. RVx-2001 Rational Vaccines William Halford Prophylactic live-attenuated HSV-2 vaccine RVx-1001 Rational Vaccines William Halford Prophylactic live-attenuated HSV-1 vaccine Vitaherpavac & Herpovax Vitafarma, Russia Inactivated HSV-1 and HSV-2 vaccine HDIT101 (Monoclonal Antibody Therapy) Heidelberg ImmunoTherapeutics GmbH Claudia Kunz, PhD anti-HSV monoclonal antibody UB-621 (Monoclonal Antibody Therapy) United BioPharma (Taiwanese Company with a branch in the US.) N/A anti-HSV monoclonal antibody
Live-attenuated non-invasive vaccines A recent development in live-attenuated HSV vaccine design is the production of replicative vaccines that are ablated for nervous system infection. These vaccines infect the respiratory mucosa where their replication and localized spread provoke a robust immune response. The safety of these vaccines is based on their inability to invade the nervous system and establish life-long latent infections, as opposed to a general attenuation. Unlike other live-attenuated designs, these vaccines are cleared from the body once the immune response from vaccination has matured. In principle, by avoiding attenuation of HSV replication in the mucosa while removing the capacity to infect the nervous system, non-invasive vaccines have the potential to break the safety-efficacy dilemma by producing the strongest possible immune response while maintaining a high degree of safety.
The VC2 non-invasive vaccine was developed by Dr. Gus Kousoulas at Louisiana State University. VC2 encodes two attenuating mutations that together reduce HSV entry into neurons. The establishment of latency is prevented in animal models such as mice, guinea pig, and rhesus monkeys.
The R2 non-invasive vaccine was developed by Drs. Gregory Smith (Northwestern University Feinberg School of Medicine), Patricia Sollars & Gary Pickard (University of Nebraska-Lincoln), and Ekaterina Heldwein (Tufts University School of Medicine). R2 vaccines retain native replication in epithelial cells but are incapable of retrograde axonal transport and invasion of the nervous system. A single dose of the R2 vaccine passively introduced on mucosal tissues protects the nervous system from future infections and affords protection against lethal encephalitic infections in mice and rats. This vaccine strategy is noted for its effectiveness against both veterinary and clinical neuroinvasive herpesviruses. Thyreos Inc was founded to develop a herpesvirus vaccine platform based on the R2 design with targeted applications in human health, companion animal health, and livestock productivity.
Live-attenuated HSV-2 vaccine Dr. William Halford at the Southern Illinois University (SIU) School of Medicine tested a live-attenuated HSV-2 ICP0∆NLS vaccine in 2016, before his death in June 2017. Vaccine attenuation is achieved by a mutation in ICP0 (ICP0∆NLS) that increases the vaccine strain's sensitivity to interferon responses and limits its replication. Already proven as safe and effective in rodents and eliciting 10 to 100 times greater protection against genital herpes than a glycoprotein D subunit vaccine, Halford's vaccine was tested outside of the United States, in St. Kitts in 20 human volunteers. All 20 of the participants self-reported an improvement in symptoms, but only 17 received and completed all three dosages. Blot tests showed a clear antibody response, which cannot be instigated by a placebo effect. However, the human trial was conducted without approval from the FDA or from the SIU Institutional Review Board.
In 2021 the vaccine candidate ICP0∆NLS, now under development as RVx-201, received the UK Innovation Passport, which provides an innovative licensing and access pathway (ILAP) within the UK health system.
Live-attenuated single-cycle replication HSV-2 vaccine A study from the Albert Einstein College of Medicine, where glycoprotein D (gD-2) was deleted from the herpes cell, showed positive results when tested in mice. Researchers deleted gD-2 from the herpes virus, which is responsible for herpes microbes entering in and out of cells. The vaccine HSV-2 ΔgD-2 is still in early stages of development and more research needs to be conducted before receiving FDA approval for clinical trials. As of 2026 the development state of the HSV-2 ΔgD-2 vaccine candidate is unclear. The vaccine was detailed tested in a research study from 2025. However, the responsible development company X-VAX has ceased operation in November 2023.
Other vaccine exploration Vitaherpavac - In patients with monotonously recurrent genital herpes infection and history of failure of standard vaccination, anti-relapse efficacy of Vitaherpavac vaccine was demonstrated after allergometry-based tailored choice of vaccine administration regimen. The used approach was associated with lower antigenic load and sensitization, more than three-fold increase in relapse-free period in 85% of treated patients and improvement of Th1-dependent immunity. The Russian vaccine Vitagerpavak — the only polyvalent vaccine in the world for treatment of the chronic gerpesvirusny infection (CGI) І and ІІ types. It is developed in scientific research institute of virology of D.I. Ivanovsky of the Russian Academy of Medical Science. More than 15 years are applied in the Russian Federation.
Discontinued vaccines